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A Genome-Wide Association Scan on the Levels of Markers of Inflammation in Sardinians Reveals Associations That Underpin Its Complex Regulation
Identifying the genes that influence levels of pro-inflammatory molecules can help to elucidate the mechanisms underlying this process. We first conducted a two-stage genome-wide association scan (GWAS) for the key inflammatory biomarkers Interleukin-6 (IL-6), the general measure of inflammation ery...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3266885/ https://www.ncbi.nlm.nih.gov/pubmed/22291609 http://dx.doi.org/10.1371/journal.pgen.1002480 |
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author | Naitza, Silvia Porcu, Eleonora Steri, Maristella Taub, Dennis D. Mulas, Antonella Xiao, Xiang Strait, James Dei, Mariano Lai, Sandra Busonero, Fabio Maschio, Andrea Usala, Gianluca Zoledziewska, Magdalena Sidore, Carlo Zara, Ilenia Pitzalis, Maristella Loi, Alessia Virdis, Francesca Piras, Roberta Deidda, Francesca Whalen, Michael B. Crisponi, Laura Concas, Antonio Podda, Carlo Uzzau, Sergio Scheet, Paul Longo, Dan L. Lakatta, Edward Abecasis, Gonçalo R. Cao, Antonio Schlessinger, David Uda, Manuela Sanna, Serena Cucca, Francesco |
author_facet | Naitza, Silvia Porcu, Eleonora Steri, Maristella Taub, Dennis D. Mulas, Antonella Xiao, Xiang Strait, James Dei, Mariano Lai, Sandra Busonero, Fabio Maschio, Andrea Usala, Gianluca Zoledziewska, Magdalena Sidore, Carlo Zara, Ilenia Pitzalis, Maristella Loi, Alessia Virdis, Francesca Piras, Roberta Deidda, Francesca Whalen, Michael B. Crisponi, Laura Concas, Antonio Podda, Carlo Uzzau, Sergio Scheet, Paul Longo, Dan L. Lakatta, Edward Abecasis, Gonçalo R. Cao, Antonio Schlessinger, David Uda, Manuela Sanna, Serena Cucca, Francesco |
author_sort | Naitza, Silvia |
collection | PubMed |
description | Identifying the genes that influence levels of pro-inflammatory molecules can help to elucidate the mechanisms underlying this process. We first conducted a two-stage genome-wide association scan (GWAS) for the key inflammatory biomarkers Interleukin-6 (IL-6), the general measure of inflammation erythrocyte sedimentation rate (ESR), monocyte chemotactic protein-1 (MCP-1), and high-sensitivity C-reactive protein (hsCRP) in a large cohort of individuals from the founder population of Sardinia. By analysing 731,213 autosomal or X chromosome SNPs and an additional ∼1.9 million imputed variants in 4,694 individuals, we identified several SNPs associated with the selected quantitative trait loci (QTLs) and replicated all the top signals in an independent sample of 1,392 individuals from the same population. Next, to increase power to detect and resolve associations, we further genotyped the whole cohort (6,145 individuals) for 293,875 variants included on the ImmunoChip and MetaboChip custom arrays. Overall, our combined approach led to the identification of 9 genome-wide significant novel independent signals—5 of which were identified only with the custom arrays—and provided confirmatory evidence for an additional 7. Novel signals include: for IL-6, in the ABO gene (rs657152, p = 2.13×10(−29)); for ESR, at the HBB (rs4910472, p = 2.31×10(−11)) and UCN119B/SPPL3 (rs11829037, p = 8.91×10(−10)) loci; for MCP-1, near its receptor CCR2 (rs17141006, p = 7.53×10(−13)) and in CADM3 (rs3026968, p = 7.63×10(−13)); for hsCRP, within the CRP gene (rs3093077, p = 5.73×10(−21)), near DARC (rs3845624, p = 1.43×10(−10)), UNC119B/SPPL3 (rs11829037, p = 1.50×10(−14)), and ICOSLG/AIRE (rs113459440, p = 1.54×10(−08)) loci. Confirmatory evidence was found for IL-6 in the IL-6R gene (rs4129267); for ESR at CR1 (rs12567990) and TMEM57 (rs10903129); for MCP-1 at DARC (rs12075); and for hsCRP at CRP (rs1205), HNF1A (rs225918), and APOC-I (rs4420638). Our results improve the current knowledge of genetic variants underlying inflammation and provide novel clues for the understanding of the molecular mechanisms regulating this complex process. |
format | Online Article Text |
id | pubmed-3266885 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-32668852012-01-30 A Genome-Wide Association Scan on the Levels of Markers of Inflammation in Sardinians Reveals Associations That Underpin Its Complex Regulation Naitza, Silvia Porcu, Eleonora Steri, Maristella Taub, Dennis D. Mulas, Antonella Xiao, Xiang Strait, James Dei, Mariano Lai, Sandra Busonero, Fabio Maschio, Andrea Usala, Gianluca Zoledziewska, Magdalena Sidore, Carlo Zara, Ilenia Pitzalis, Maristella Loi, Alessia Virdis, Francesca Piras, Roberta Deidda, Francesca Whalen, Michael B. Crisponi, Laura Concas, Antonio Podda, Carlo Uzzau, Sergio Scheet, Paul Longo, Dan L. Lakatta, Edward Abecasis, Gonçalo R. Cao, Antonio Schlessinger, David Uda, Manuela Sanna, Serena Cucca, Francesco PLoS Genet Research Article Identifying the genes that influence levels of pro-inflammatory molecules can help to elucidate the mechanisms underlying this process. We first conducted a two-stage genome-wide association scan (GWAS) for the key inflammatory biomarkers Interleukin-6 (IL-6), the general measure of inflammation erythrocyte sedimentation rate (ESR), monocyte chemotactic protein-1 (MCP-1), and high-sensitivity C-reactive protein (hsCRP) in a large cohort of individuals from the founder population of Sardinia. By analysing 731,213 autosomal or X chromosome SNPs and an additional ∼1.9 million imputed variants in 4,694 individuals, we identified several SNPs associated with the selected quantitative trait loci (QTLs) and replicated all the top signals in an independent sample of 1,392 individuals from the same population. Next, to increase power to detect and resolve associations, we further genotyped the whole cohort (6,145 individuals) for 293,875 variants included on the ImmunoChip and MetaboChip custom arrays. Overall, our combined approach led to the identification of 9 genome-wide significant novel independent signals—5 of which were identified only with the custom arrays—and provided confirmatory evidence for an additional 7. Novel signals include: for IL-6, in the ABO gene (rs657152, p = 2.13×10(−29)); for ESR, at the HBB (rs4910472, p = 2.31×10(−11)) and UCN119B/SPPL3 (rs11829037, p = 8.91×10(−10)) loci; for MCP-1, near its receptor CCR2 (rs17141006, p = 7.53×10(−13)) and in CADM3 (rs3026968, p = 7.63×10(−13)); for hsCRP, within the CRP gene (rs3093077, p = 5.73×10(−21)), near DARC (rs3845624, p = 1.43×10(−10)), UNC119B/SPPL3 (rs11829037, p = 1.50×10(−14)), and ICOSLG/AIRE (rs113459440, p = 1.54×10(−08)) loci. Confirmatory evidence was found for IL-6 in the IL-6R gene (rs4129267); for ESR at CR1 (rs12567990) and TMEM57 (rs10903129); for MCP-1 at DARC (rs12075); and for hsCRP at CRP (rs1205), HNF1A (rs225918), and APOC-I (rs4420638). Our results improve the current knowledge of genetic variants underlying inflammation and provide novel clues for the understanding of the molecular mechanisms regulating this complex process. Public Library of Science 2012-01-26 /pmc/articles/PMC3266885/ /pubmed/22291609 http://dx.doi.org/10.1371/journal.pgen.1002480 Text en This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. https://creativecommons.org/publicdomain/zero/1.0/ This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration, which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. |
spellingShingle | Research Article Naitza, Silvia Porcu, Eleonora Steri, Maristella Taub, Dennis D. Mulas, Antonella Xiao, Xiang Strait, James Dei, Mariano Lai, Sandra Busonero, Fabio Maschio, Andrea Usala, Gianluca Zoledziewska, Magdalena Sidore, Carlo Zara, Ilenia Pitzalis, Maristella Loi, Alessia Virdis, Francesca Piras, Roberta Deidda, Francesca Whalen, Michael B. Crisponi, Laura Concas, Antonio Podda, Carlo Uzzau, Sergio Scheet, Paul Longo, Dan L. Lakatta, Edward Abecasis, Gonçalo R. Cao, Antonio Schlessinger, David Uda, Manuela Sanna, Serena Cucca, Francesco A Genome-Wide Association Scan on the Levels of Markers of Inflammation in Sardinians Reveals Associations That Underpin Its Complex Regulation |
title | A Genome-Wide Association Scan on the Levels of Markers of Inflammation in Sardinians Reveals Associations That Underpin Its Complex Regulation |
title_full | A Genome-Wide Association Scan on the Levels of Markers of Inflammation in Sardinians Reveals Associations That Underpin Its Complex Regulation |
title_fullStr | A Genome-Wide Association Scan on the Levels of Markers of Inflammation in Sardinians Reveals Associations That Underpin Its Complex Regulation |
title_full_unstemmed | A Genome-Wide Association Scan on the Levels of Markers of Inflammation in Sardinians Reveals Associations That Underpin Its Complex Regulation |
title_short | A Genome-Wide Association Scan on the Levels of Markers of Inflammation in Sardinians Reveals Associations That Underpin Its Complex Regulation |
title_sort | genome-wide association scan on the levels of markers of inflammation in sardinians reveals associations that underpin its complex regulation |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3266885/ https://www.ncbi.nlm.nih.gov/pubmed/22291609 http://dx.doi.org/10.1371/journal.pgen.1002480 |
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